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Summary Medicinal chemistry and Biophysics
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Medicinal chemistry & biophysicsIntroduction and thermodynamics, Matthew, 27-09-2021
Biophysics is the use of light, sound or particle emission (waves) to study a bio sample.
The 3D structure of drugs determines the biological activity of drugs. Because of the 3D shape the
membrane passage, binding to targets, metabolism and pharmacokinetics are different for each
drug.
Drugs need to be able to pass multiple lipid layers and thereby interact with the target site or get
metabolised in the liver or bloodstream.
A polar drug will only interact
with the watery environment or
the charged parts of the
membrane. A non-polar drug will
get stuck in the membrane
resulting in an inactive drug as
well. Therefore you want an
amphiphilic drug, this has a polar
nature and a non-polar nature.
The pH of solute chosen to generate neutral molecules is the log P value. This is a measure of
lipophilicity.
The five rules of Lipinski are:
- Molecular mass less than 500 Da
- logP less than 5
- less than ten hydrogen bond acceptors (this is 2 times 5; so 2 rules)
- less than five hydrogen bond donors
Paul Ehrlich introduced the
idea that the biological
effect of almost all
compounds was due to it
binding to a target which
was not an alcohol
receptor. Drugs will bind to
their target as a key will fit
into a lock. The binding
process however, is dynamic.
Thermodynamics describe the equilibrium state (K). Kinetics describe the rate (speed) of the process
(bound to unbound) (k). The more stable the system is the more the equilibrium will be shifted
towards the right. Therefore the thermodynamics will be larger.
A covalent bond is a bond that will not dissociate. There will thus not be an equilibrium.
The majority of drugs however, will form non-covalent bonds. This means that there can be
dissociation or there can be an equilibrium.
,The energy of drugs can be described by Gibb’s free energy. Gibbs free energy is the energy required
to build the system from nothing. It is the energy required to create a state from vacuum. Important
descriptor of the changes that occur over a binding or reaction process.
Drug designing is all about making the ΔG as small as possible. The change in the ΔG has a heat
component and an entropy component. Heat (ΔH) > 0 energy (heat) is absorbed -> endothermic
reaction, Heat (ΔH) < 0 energy (heat) is released -> exothermic reaction. Entropy (ΔS) is a measure of
the ordering of the system.
Successful binding requires a change in energy coming from entropy and heat. Non-covalent binding
is achieved by many simultaneous interactions between the ligand and the macromolecule.
Electrostatic interactions are interactions between opposite charges and equal charges will repel.
Electrostatic interactions are ion-ion dipole interactions like hydrogen bonds. These contribute to
enthalpy.
The role of entropy in binding is
through reduced ligand flexibility
leading to lower entropy. Removal
of solvation shell around both
bindings partners leading to
increased entropy.
Medicinal Chemistry:
Intro, Alexander
Dömling, 28-09-2021
Medicinal chemistry is a discipline
at the intersection and
pharmacology involved with
designing, synthesizing and developing pharmaceutical drugs.
New drugs are found during the discovery stage whereafter these will be clinically developed and
when approved by the medicine agency they become drug products that can be used for clinical
application.
Properties that a good drug has to consists of are: pharmacological properties and drug-like
properties. Pharmacological properties are: target binding, target residence time and target
selectivity. Drug-like properties are bioavailability, permeability, stability and the solubility. A high
quality drug will consist both of pharmacological properties and drug-like properties.
Evolution of drug discovery technologies over time have drastically changed, pharmacology screening
has changed from direct testing in living systems to in vitro high-throughput screening. Initial leads
for optimization have changed from natural products and natural ligands to large libraries of diverse
structures. Compound design has been enhanced from structure-activity relationships by the
addition of x-ray crystallography and NMR binding studies and computational modelling. Lead
optimization chemistry has been enhanced from one-at-a-time synthesis by the addition of parallel
synthesis. Traditional sequential experiments have been enhanced with parallel experiments, such as
microtiter plate formats.
Drug-like properties can be divided into structural properties, physicochemical properties,
biochemical properties and pharmacokinetics and toxicity. Structural properties are:
, - Hydrogen bonding
- Polar surface area
- Lipophilicity
- Shape
- Molecular weight
- Reactivity
- pKa
Physicochemical properties are:
- Solubility
- Permeability
- Chemical stability
Biochemical properties are:
- Metabolism (phase I and II)
- Protein and tissue binding
- Transport (uptake and efflux)
Pharmacokinetics (PK) and toxicity are:
- Clearance
- Half-life
- Bioavailability
- Drug-drug interaction
- LD50
Drug discovery first starts of by exploring the possible options that the drug has. These options will
have a few leads and will thus lead to a lead selection of possibilities. These possibilities are then
tried to optimise resulting eventually into development selection.
DMTA (design-make-test-analyse) cycle is used for the design of drugs and varies per company.
About 20-30 cycles are needed to obtain a lead for new potential drugs.
The lifetime of a drug takes several years. Until the clinical R&D the pharmaceutical company has
only costs the company money. When the drug is efficacious, the drug will start earning money back.
The research and development are very costly.
Some drugs that come to the market fail, earlier there was a lot of failure on pharmacokinetics
however this has progressed to improve significantly over the years. Pharmacokinetics are thus
optimized in the research and development phase and thereby the drug has more chance of
succeeding on the pharmacokinetic aspect. Lack of efficacy is the main reason for failure drug
discovery and development projects.
A lot of products are failing preclinically, this is not a
problem since not so much money has been put into
the project. However, the further you go into the
development of the drug the reason for efficacy and
clinical safety become bigger. Most clinical trials fail in
the transition between phase II and phase III which is
unfortunate because a lot of money was spend into the
compound development.
, Drug discovery and developing costs have drastically risen over the last years and therefore the drug
prices are inflation adjusted and includes failures of other drugs.
Poor properties can cause poor discovery research. Low or inconsistent bioactivity responses for in
vitro bioassays can be due to precipitation, owing to low solubility of the compound in the bioassay
medium or in dilutions prior to the assy. Low activity in bioassays may be due to chemical instability
of the compound in the test matrix. An unexpectedly high drop in activity can result when
transitioning from enzyme or receptor activity assays to cell-based assays. This can be due to poor
permeability of the compound through the cell membrane, which must be penetrated for the
compound to reach intracellular targets. Compounds may be unstable or insoluble in the DMSO
solutions that are stored in microtiter plates and experience freeze-thaw cycles, or they may be
exposed to various physicochemical conditions in the laboratory. Poor efficacy of a central nervous
system drug in vivo may be due to poor penetration of the blood-brain barrier. Poor efficacy in vivo
may be due to low concentrations in the plasma and target tissue because of poor PK, low
bioavailability, or instability in the blood.
The primary focus on activity can yield
compounds that are very effective as ligands
of the target protein, but the properties may
be inadequate for the compounds to become
successful drugs. Diverse ensemble of crucial
elements must be simultaneously monitored
and kept in balance in order to achieve
success.
The structure-activity relationship (SAR) gives
answer to the question of how the affinity
changes when chemical structure of the
compound is changed and how these changes will relate to target selectivity.
Structure-property relationships (SPR) are developed to:
- Better planning, execution, and interpretation of discovery experiments
- Reduced discovery time lag from not having to fix property-based problems at a later time
- Faster and more economical pharmaceutical development
- Candidates with lower risk and higher future value
- Longer patent life
- Higher patient acceptance and compliance
The difference between SAR and SPR is that SAR is related to change in affinity upon change in
chemical structure. SPR focusses on the change in drug-properties upon change in structure. SAR and
SPR are used simultaneously to achieve the best possible drug.
Process of drug discovery balances search for molecules that have structural features that produce:
- Strong target binding using structure-based design and the structure-activity relationship
(SAR)
- High performance at in vivo barriers, using property-based design and the structure-property
relationship (SPR)
A common goal of pharmaceutical researchers is to develop a drug dosage form that is a low-dose
tablet with a dosing regimen of oral administration once per day. Oral administration has reasonable
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